Maternal alcohol consumption during pregnancy and offspring epigenome-wide DNA methylation: findings from six general population-based birth cohorts

Some evidence suggests that light-to-moderate alcohol consumption during pregnancy is associated with adverse outcomes in the offspring, but the precise biological mechanisms underlying such associations are currently unknown. Epigenetic modifications have been suggested as one potential explanation. Within the Pregnancy and Childhood Epigenetics (PACE) consortium, we performed meta-analysis to combine information from six population-based birth cohort studies to investigate DNA methylation at over 450,000 sites in the cord blood of newborns differentially exposed to alcohol in utero. We were primarily interested in the effects of sustained consumption throughout pregnancy (data available for five cohorts, 3,075 mother-child pairs), which represents a prolonged prenatal exposure to alcohol, but we also explored binge-drinking and timing-specific exposures. In addition to looking for differential methylation at individual CpG sites, we also used two different methods, Comb-P and DMRcate, to identify differentially methylated regions (DMRs). We found no strong evidence of association between any of our alcohol exposure measures and DNA methylation at any individual CpG site. Using Comb-P, we identified 19 DMRs in the offspring of mothers who drank throughout pregnancy compared to the offspring of mothers who gave up drinking at the start of pregnancy, but these were not validated using DMRcate. In this multi-cohort study of the general population we found no evidence that maternal alcohol consumption during pregnancy is associated with offspring cord blood DNA methylation, which is in stark contrast to the multiple, strong associations that previous studies have found for maternal smoking. However, it is possible that a combination of a larger sample size, higher doses, different timings of exposure and a more global assessment of genomic DNA methylation might show evidence of association.

[1]  G. Smith,et al.  Association between Breastfeeding and DNA Methylation over the Life Course: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) , 2019, bioRxiv.

[2]  M. Delgado-Rodríguez,et al.  Systematic review and meta-analysis. , 2017, Medicina intensiva.

[3]  R. Marioni,et al.  A DNA methylation biomarker of alcohol consumption , 2016, Molecular Psychiatry.

[4]  B. Laufer,et al.  Long-term alterations to DNA methylation as a biomarker of prenatal alcohol exposure: From mouse models to human children with fetal alcohol spectrum disorders. , 2017, Alcohol.

[5]  D. Postma,et al.  Epigenome-Wide Meta-Analysis of Methylation in Children Related to Prenatal NO2 Air Pollution Exposure , 2016, Environmental health perspectives.

[6]  John W. Tukey,et al.  Exploratory data analysis , 1977, Addison-Wesley series in behavioral science : quantitative methods.

[7]  G. Davey Smith,et al.  Pre-conception and prenatal alcohol exposure from mothers and fathers drinking and head circumference: results from the Norwegian Mother-Child Study (MoBa) , 2016, Scientific Reports.

[8]  J. Donovan,et al.  Effects of low alcohol consumption on pregnancy and childhood outcomes: a systematic review and meta-analysis , 2016, The Lancet.

[9]  M. Cynader,et al.  DNA methylation signature of human fetal alcohol spectrum disorder , 2016, Epigenetics & Chromatin.

[10]  E. Birney,et al.  Epigenome-wide Association Studies and the Interpretation of Disease -Omics , 2016, PLoS genetics.

[11]  Jingyu Liu,et al.  Correspondence of DNA Methylation Between Blood and Brain Tissue and Its Application to Schizophrenia Research. , 2016, Schizophrenia bulletin.

[12]  S. Lewis,et al.  Moderate alcohol drinking in pregnancy increases risk for children's persistent conduct problems: causal effects in a Mendelian randomisation study , 2015, Journal of child psychology and psychiatry, and allied disciplines.

[13]  T. Toth,et al.  Prepregnancy Low to Moderate Alcohol Intake Is Not Associated with Risk of Spontaneous Abortion or Stillbirth. , 2015, The Journal of nutrition.

[14]  J. Mill,et al.  Interindividual methylomic variation across blood, cortex, and cerebellum: implications for epigenetic studies of neurological and neuropsychiatric phenotypes , 2015, Epigenetics.

[15]  F. Hartwig,et al.  From stem cells to the law courts: DNA methylation, the forensic epigenome and the possibility of a biosocial archive. , 2015, International journal of epidemiology.

[16]  Allyson L. Lister,et al.  Data Resource Profile: Accessible Resource for Integrated Epigenomic Studies (ARIES). , 2015, International journal of epidemiology.

[17]  L. Poston,et al.  Prevalence and predictors of alcohol use during pregnancy: findings from international multicentre cohort studies , 2015, BMJ Open.

[18]  J. V. van Meurs,et al.  DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring , 2015, International journal of epidemiology.

[19]  A. Baccarelli,et al.  Cohort profile: project viva. , 2015, International journal of epidemiology.

[20]  Tom R. Gaunt,et al.  The Avon Longitudinal Study of Parents and Children (ALSPAC): an update on the enrolled sample of index children in 2019 , 2019, Wellcome open research.

[21]  Peter L Molloy,et al.  De novo identification of differentially methylated regions in the human genome , 2015, Epigenetics & Chromatin.

[22]  O. Franco,et al.  The Generation R Study: Biobank update 2015 , 2014, European Journal of Epidemiology.

[23]  G. Smith,et al.  Approaches for drawing causal inferences from epidemiological birth cohorts: a review. , 2014, Early human development.

[24]  Steve Horvath,et al.  Gene expression signatures affected by alcohol-induced DNA methylomic deregulation in human embryonic stem cells. , 2014, Stem cell research.

[25]  J. Niclasen.  Drinking or not drinking in pregnancy: the multiplicity of confounding influences. , 2014, Alcohol and alcoholism.

[26]  P. Kearney,et al.  The effect of moderate gestational alcohol consumption during pregnancy on speech and language outcomes in children: a systematic review , 2014, Systematic Reviews.

[27]  M. Cogswell,et al.  The association of mild, moderate, and binge prenatal alcohol exposure and child neuropsychological outcomes: a meta-analysis. , 2014, Alcoholism, clinical and experimental research.

[28]  Beau Dabbs,et al.  Summary and discussion of : “ Controlling the False Discovery Rate : A Practical and Powerful Approach to Multiple Testing , 2014 .

[29]  Raivo Kolde,et al.  DNA methylome profiling of human tissues identifies global and tissue-specific methylation patterns , 2014, Genome Biology.

[30]  R. Irizarry,et al.  Accounting for cellular heterogeneity is critical in epigenome-wide association studies , 2014, Genome Biology.

[31]  Haroon Naeem,et al.  Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array , 2014, BMC Genomics.

[32]  S. Horvath.  DNA methylation age of human tissues and cell types , 2013, Genome Biology.

[33]  M. Kogevinas,et al.  Maternal dietary intake of dioxins and polychlorinated biphenyls and birth size in the Norwegian Mother and Child Cohort Study (MoBa). , 2013, Environment international.

[34]  C. Lehmann,et al.  Alcohol exposure during development: Impact on the epigenome , 2013, International Journal of Developmental Neuroscience.

[35]  L. Poston,et al.  Association Between Maternal Alcohol Consumption in Early Pregnancy and Pregnancy Outcomes , 2013, Obstetrics and gynecology.

[36]  S. Ring,et al.  Prenatal alcohol exposure and offspring cognition and school performance. A ‘Mendelian randomization’ natural experiment , 2013, International journal of epidemiology.

[37]  R. Gray.  Low‐to‐moderate alcohol consumption during pregnancy and child development – moving beyond observational studies , 2013, BJOG : an international journal of obstetrics and gynaecology.

[38]  K. Northstone,et al.  Sources of Vitamin A in the Diets of Pre-School Children in the Avon Longitudinal Study of Parents and Children (ALSPAC) , 2013, Nutrients.

[39]  D. Lawlor,et al.  Cohort Profile: The ‘Children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children , 2012, International journal of epidemiology.

[40]  D. Lawlor,et al.  Cohort Profile: The Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort , 2012, International journal of epidemiology.

[41]  C. Hertzman,et al.  Epigenetic vestiges of early developmental adversity: childhood stress exposure and DNA methylation in adolescence. , 2013, Child development.

[42]  S. Ring,et al.  Fetal Alcohol Exposure and IQ at Age 8: Evidence from a Population-Based Birth-Cohort Study , 2012, PloS one.

[43]  Brent S. Pedersen,et al.  Comb-p: software for combining, analyzing, grouping and correcting spatially correlated P-values , 2012, Bioinform..

[44]  Kenneth J Rothman,et al.  Predictors of preconceptional folic acid or multivitamin supplement use: a cross-sectional study of Danish pregnancy planners , 2012, Clinical epidemiology.

[45]  J. Kere,et al.  Differential DNA Methylation in Purified Human Blood Cells: Implications for Cell Lineage and Studies on Disease Susceptibility , 2012, PloS one.

[46]  C. Collier,et al.  Folic Acid Transport to the Human Fetus Is Decreased in Pregnancies with Chronic Alcohol Exposure , 2012, PloS one.

[47]  Devin C. Koestler,et al.  DNA methylation arrays as surrogate measures of cell mixture distribution , 2012, BMC Bioinformatics.

[48]  E. Mohammadi,et al.  Barriers and facilitators related to the implementation of a physiological track and trigger system: A systematic review of the qualitative evidence , 2017, International journal for quality in health care : journal of the International Society for Quality in Health Care.

[49]  G. Davey Smith,et al.  Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. , 2012, International journal of epidemiology.

[50]  V. Medici,et al.  Aberrant Hepatic Methionine Metabolism and Gene Methylation in the Pathogenesis and Treatment of Alcoholic Steatohepatitis , 2011, International journal of hepatology.

[51]  Hunter B. Fraser,et al.  Population-specificity of human DNA methylation , 2012, Genome Biology.

[52]  J. Rehm,et al.  Dose–response relationship between alcohol consumption before and during pregnancy and the risks of low birthweight, preterm birth and small for gestational age (SGA)—a systematic review and meta‐analyses , 2011, BJOG : an international journal of obstetrics and gynaecology.

[53]  M. Esteller,et al.  Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome , 2011, Epigenetics.

[54]  A. Paoloni-Giacobino,et al.  Prenatal exposure to ethanol: a specific effect on the H19 gene in sperm. , 2011, Reproductive toxicology.

[55]  D. Lawlor,et al.  Associations of gestational weight gain with maternal body mass index, waist circumference, and blood pressure measured 16 y after pregnancy: the Avon Longitudinal Study of Parents and Children (ALSPAC) , 2011, The American journal of clinical nutrition.

[56]  U. Kesmodel,et al.  Prenatal alcohol exposure – a systematic review of the effects on child motor function , 2010, Acta obstetricia et gynecologica Scandinavica.

[57]  William N. Venables,et al.  Modern Applied Statistics with S , 2010 .

[58]  A. Hofman,et al.  The Generation R Study: design and cohort update 2010 , 2010, European Journal of Epidemiology.

[59]  Witold R. Rudnicki,et al.  Feature Selection with the Boruta Package , 2010 .

[60]  Wolfgang Viechtbauer,et al.  Conducting Meta-Analyses in R with the metafor Package , 2010 .

[61]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[62]  J. Sweatt,et al.  Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene , 2009, Biological Psychiatry.

[63]  R. Stolk,et al.  Cohort Profile: the GECKO Drenthe study, overweight programming during early childhood. , 2008, International journal of epidemiology.

[64]  F. Schmidt.  Meta-Analysis , 2008 .

[65]  P. Brocklehurst,et al.  Systematic review of effects of low–moderate prenatal alcohol exposure on pregnancy outcome , 2007, BJOG : an international journal of obstetrics and gynaecology.

[66]  P. Magnus,et al.  Cohort profile: the Norwegian Mother and Child Cohort Study (MoBa). , 2006, International journal of epidemiology.

[67]  H. Meltzer,et al.  The biobank of the Norwegian mother and child cohort Study: A resource for the next 100 years , 2006, European Journal of Epidemiology.

[68]  C. Goodlett,et al.  Alcohol Teratogenesis: Mechanisms of Damage and Strategies for Intervention , 2005, Experimental biology and medicine.

[69]  Gideon Koren,et al.  Fetal Alcohol Spectrum Disorder , 2010 .

[70]  J. Jacobson,et al.  Maternal recall of alcohol, cocaine, and marijuana use during pregnancy. , 1991, Neurotoxicology and teratology.

[71]  C. Goodlett,et al.  Blood alcohol concentration and severity of microencephaly in neonatal rats depend on the pattern of alcohol administration. , 1988, Alcohol.

[72]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[73]  S. Clarren.  Recognition of fetal alcohol syndrome. , 1981, JAMA.

[74]  David W. Smith,et al.  Recognition of the fetal alcohol syndrome in early infancy. , 1973, Lancet.